Use of fk506 and analogues for treating allergic diseases

ABSTRACT

The present invention provides, in the treatment of allergic diseases using an interleukin 2 inhibitor, particularly a macrolide compound such as FK506, a method of treating an allergic disease, which includes setting a leading period for pre-administration of an interleukin 2 inhibitor.

This application is based on application No. 60/331,722 filed in UnitedStates of America, the content of which is incorporated hereinto byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for treating allergicdiseases.

BACKGROUND ART

When a foreign matter invades the body, an antibody or sensitizedlymphocyte is generated by an immune response. The antibody orsensitized lymphocyte reacts with the foreign matter when it invadesagain, whereby the foreign matter is removed or attenuated. This is theso-called “immunity”. When the reaction proceeds inversely to damage thebody, it is called an “allergy”.

An allergic reaction was classified into IgE dependent anaphylactic type(I type), cytotoxic type (II type), immune complex type (III type), andcellular immunity type (IV type) by Coombs and Gell (1963) based on themechanism of immune reaction. It is considered that these reaction typesare involved in a complicated manner to cause allergic diseases in theliving body.

The I type allergy is a general name for hypersensitiveness caused bythe reaction with IgE antibody upon contact with an allergen, and thistype is also called an atopic disease. For example, bronchial asthma,allergic rhinitis, allergic conjunctivitis, atopic dermatitis, foodallergy, and a part of drug allergy fall under the atopic diseases.

In the meantime, a macrolide compound, such as FK506, and cyclosporinsare known to be effective for the treatment of allergic diseases such asallergic conjunctivitis, spring catarrh, atopic dermatitis and the like(WO 92/19278 etc.).

DISCLOSURE OF THE INVENTION

The present inventor has conducted intensive studies and surprisinglyfound that, in the treatment of allergic diseases using an interleukin 2(hereinafter sometimes referred to simply as IL-2) inhibitor, expressionof the effect is drastically increased by setting a leading period forpre-administration of an IL-2 inhibitor, which resulted in thecompletion of the present invention.

Accordingly, the present invention provides the following.

-   (1) A pharmaceutical agent for pre-administration, which comprises    an interleukin 2 inhibitor (IL-2 inhibitor) as an active ingredient,    and which is used for treating an allergic disease, wherein the    treatment includes a leading period for pre-administration of the    IL-2 inhibitor to a subject in need of the treatment of allergic    disease, and administration of an effective amount of an IL-2    inhibitor.

(2) The pharmaceutical agent of (1), wherein the IL-2 inhibitor is amacrolide compound or a cyclosporin.

(3) The pharmaceutical agent of (2), wherein the macrolide compound is atricyclo compound (I) of the following formula (hereinafter sometimesreferred to simply as tricyclo compound (I));

wherein adjacent pairs of R¹ and R², R³ and R⁴, and R⁵ and R⁶ eachindependently

-   -   a) consist of two adjacent hydrogen atoms, wherein R² is        optionally alkyl, or    -   b) form another bond between carbon atoms binding with the        members of each pairs;    -   R⁷ is hydrogen atom, hydroxy, alkyloxy or protected hydroxy, or        may form oxo with R¹;    -   R⁸ and R⁹ each independently show hydrogen atom or hydroxy;    -   R¹⁰ is hydrogen atom, alkyl, alkenyl, alkyl substituted by one        or more hydroxy, alkenyl substituted by one or more hydroxy, or        alkyl substituted by oxo;    -   X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen        atom), or a group of the formula —CH₂O—;    -   Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen        atom), or a group of the formula N—NR¹¹R¹² or N—OR¹³;    -   R¹¹ and R¹² each independently show hydrogen atom, alkyl, aryl        or tosyl;    -   R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ each        independently show hydrogen atom or alkyl;    -   R²⁴ is an optionally substituted ring that may contain one or        more hetero atom(s); and    -   n is 1 or 2.

In addition to the meaning noted above, Y, R¹⁰ and R²³ may form,together with the carbon atom they bind with, a saturated or unsaturated5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atomand/or oxygen atom, wherein the heterocyclic group may be substituted byone or more group(s) selected from the group consisting of alkyl,hydroxy, alkyloxy, benzyl, a group of the formula —CH₂Se(C₆H₅), andalkyl substituted by one or more hydroxy, or a pharmaceuticallyacceptable salt thereof.

-   (4) The pharmaceutical agent of (2) or (3), wherein the macrolide    compound is FK506.-   (5) The pharmaceutical agent of (1), wherein the IL-2 inhibitor is a    preparation for local administration, especially a preparation for    local administration to the eye or the nose.-   (6) The pharmaceutical agent of (1), wherein the allergic disease is    allergic conjunctivitis.-   (7) The pharmaceutical agent of (1), wherein the allergic disease is    seasonal allergic disease, especially seasonal allergic    conjunctivitis.-   (8) A pharmaceutical composition for pre-administration, which    comprises an IL-2 inhibitor as an active ingredient and a    pharmaceutically acceptable carrier, and which is used for treating    an allergic disease, wherein the treatment includes a leading period    for pre-administration of the IL-2 inhibitor to a subject in need of    the treatment of allergic disease, and administration of an    effective amount of an IL-2 inhibitor.-   (9) The pharmaceutical composition of (8), wherein the IL-2    inhibitor is a macrolide compound or a cyclosporin.-   (10) The pharmaceutical composition of (9), wherein the macrolide    compound is a tricyclo compound (I), or a pharmaceutically    acceptable salt thereof.-   (11) The pharmaceutical composition of (9) or (10), wherein the    macrolide compound is FK506.-   (12) The pharmaceutical composition of (8), wherein the IL-2    inhibitor is a preparation for local administration, especially a    preparation for local administration to the eye or the nose.-   (13) The pharmaceutical composition of (8), wherein the allergic    disease is allergic conjunctivitis.-   (14) The pharmaceutical composition of (8), wherein the allergic    disease is seasonal allergic disease, especially seasonal allergic    conjunctivitis.-   (15) A method for treating an allergic disease, which comprises    pre-administering an IL-2 inhibitor for a leading period and then    administering an effective amount of an IL-2 inhibitor to a subject    in need of a treatment of an allergic disease.-   (16) The method of (15), wherein the IL-2 inhibitor is a macrolide    compound or a cyclosporin.-   (17) The method of (16), wherein the macrolide compound is a    tricyclo compound (I), or a pharmaceutically acceptable salt    thereof.-   (18) The method of (16) or (17), wherein the macrolide compound is    FK506.-   (19) The method of (15), wherein the IL-2 inhibitor is a preparation    for local administration, especially a preparation for local    administration to the eye or to the nose.-   (20) The method of (15), wherein the allergic disease is allergic    conjunctivitis.-   (21) The method of (15), wherein the allergic disease is a seasonal    allergic disease, especially seasonal allergic conjunctivitis.-   (22) Use of an IL-2 inhibitor for the production of a pharmaceutical    composition for pre-administration, which comprises the IL-2    inhibitor as an active ingredient and a pharmaceutically acceptable    carrier, and which is used for treating an allergic disease, wherein    the treatment includes a leading period for pre-administration of    the IL-2 inhibitor to a subject in need of the treatment of allergic    disease, and administration of an effective amount of an IL-2    inhibitor.-   (23) The use of (22), wherein the IL-2 inhibitor is a macrolide    compound or a cyclosporin.-   (24) The use of (23), wherein the macrolide compound is a tricyclo    compound (I), or a pharmaceutically acceptable salt thereof.-   (25) The use of (23) or (24), wherein the macrolide compound is    FK506.-   (26) The use of (22), wherein the IL-2 inhibitor is a preparation    for local administration, especially a preparation for local    administration to the eye or the nose.-   (27) The use of (22), wherein the allergic disease is allergic    conjunctivitis.-   (28) The use of (22), wherein the allergic disease is seasonal    allergic disease, especially seasonal allergic conjunctivitis.-   (29) A commercial package comprising the pharmaceutical composition    of any of the above-mentioned (8) to (14) and a written matter    associated therewith, the written matter stating that the    pharmaceutical composition can or should be used for    pre-administration for treating allergic diseases, wherein the    treatment includes a leading period for pre-administration of the    IL-2 inhibitor to a subject in need of the treatment of allergic    disease, and administration of an effective amount of an IL-2    inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

The IL-2 inhibitor to be used in the present invention is notparticularly limited and may be any as long as it has an IL-2 inhibitoryactivity. One example thereof is an IL-2 production inhibitor. Anotherexample is an IL-2 signal transduction inhibitor. Preferable examplesthereof include macrolide compounds such as FK506, Ascomycin derivative,Rapamycin derivative and the like, and cyclosporins and the like.

Specific examples of macrolide compound include tricyclo compound (I) ofthe following formula and a pharmaceutically acceptable salt thereof.

wherein adjacent pairs of R¹ and R², R³ and R⁴, and R⁵ and R⁶ eachindependently

-   -   a) consist of two adjacent hydrogen atoms, wherein R² is        optionally alkyl, or    -   b) form another bond between carbon atoms binding with the        members of each pairs;    -   R⁷ is hydrogen atom, hydroxy, alkyloxy or protected hydroxy, or        may form oxo with R¹;    -   R⁸ and R⁹ each independently show hydrogen atom or hydroxy;    -   R¹⁰ is hydrogen atom, alkyl, alkenyl, alkyl substituted by one        or more hydroxy, alkenyl substituted by one or more hydroxy or        alkyl substituted by oxo;    -   X is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen        atom), or a group of the formula —CH₂O—;    -   Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogen        atom), or a group of the formula N—NR¹¹R¹² or N—OR¹³;    -   R¹¹ and R¹² each independently show hydrogen atom, alkyl, aryl        or tosyl;    -   R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ each        independently show hydrogen atom or alkyl;    -   R²⁴ is an optionally substituted ring that may contain one or        more hetero atom(s); and    -   n is 1 or 2.

In addition to the meaning noted above, Y, R¹⁰ and R²³ may form,together with the carbon atom they bind with, a saturated or unsaturated5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atomand/or oxygen atom, wherein the heterocyclic group may be substituted byone or more group(s) selected from alkyl, hydroxy, alkyloxy, benzyl, agroup of the formula —CH₂Se(C₆H₅), and alkyl substituted by one or morehydroxy.

Preferable R²⁴ is, for example, cyclo(C₅-C₇)alkyl optionally havingsuitable substituent, such as the following.

-   (a) 3,4-dioxocyclohexyl,-   (b) 3-R²⁰-4-R²¹-cyclohexyl,    -   wherein R²⁰ is hydroxy, alkyloxy or —OCH₂OCH₂CH₂OCH₃, and    -   R²¹ is hydroxy, —OCN, alkyloxy, heteroaryloxy optionally having        suitable substituent, —OCH₂OCH₂CH₂OCH₃, protected hydroxy,        chloro, bromo, iodo, aminooxalyloxy, azide,        p-tolyloxythiocarbonyloxy, or R²⁵R²⁶CHCOO— (wherein R²⁵ is        hydroxy optionally protected where desired or protected amino,        and R²⁶ is hydrogen atom or methyl) or R²⁰ and R²¹ in        combination form an oxygen atom of epoxide ring, and-   (c) cyclopentyl wherein cyclopentyl is substituted by methoxymethyl,    protected hydroxymethyl where desired, acyloxymethyl (wherein acyl    moiety is optionally quaternized dimethylamino where desired or    optionally esterified carboxy), one or more optionally protected    amino and/or hydroxy, or aminooxalyloxymethyl. Preferable example    includes 2-formyl-cyclopentyl.

The definition of each symbol used in the formula (I), specific examplesthereof and preferable embodiments thereof are explained in detail inthe following.

“Lower” means that a group has 1 to 6 carbon atoms unless otherwiseindicated.

Preferable examples of the alkyl moiety of “alkyl” and “alkyloxy”include linear or branched aliphatic hydrocarbon residue, such as loweralkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,neopentyl, hexyl and the like).

Preferable examples of “alkenyl” include linear or branched aliphatichydrocarbon residue having one double bond, such as lower alkenyl (e.g.,vinyl, propenyl (e.g., allyl and the like), butenyl, methylpropenyl,pentenyl, hexenyl and the like).

Preferable examples of “aryl” include phenyl, tolyl, xylyl, cumenyl,mesityl, naphthyl and the like.

Preferable examples of the protective group for “protected hydroxy” and“protected amino” include 1-(lower alkylthio) (lower)alkyl such as loweralkylthiomethyl (e.g., methylthiomethyl, ethylthiomethyl,propylthiomethyl, isopropylthiomethyl, butylthiomethyl,isobutylthiomethyl, hexylthiomethyl and the like), with more preferencegiven to C₁-C₄ alkylthiomethyl and most preference given tomethylthiomethyl;

-   -   tri-substituted silyl such as tri(lower)alkylsilyl (e.g.,        trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl        dimethylsilyl, tri-tert-butylsilyl and the like), and lower        alkyldiarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl,        propyldiphenylsilyl, tert-butyldiphenylsilyl and the like), with        more preference given to tri(C₁-C₄)alkylsilyl and C₁-C₄        alkyldiphenylsilyl, and most prefererence given to        tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl;    -   acyl such as aliphatic acyl, aromatic acyl and aliphatic acyl        substituted by aromatic group, which are derived from carboxylic        acid, sulfonic acid and carbamic acid; and the like.

The aliphatic acyl is exemplified by lower alkanoyl optionally havingone or more suitable substituent(s) (e.g., carboxy) such as formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl,carboxyhexanoyl and the like;

-   -   cyclo(lower)alkyloxy(lower)alkanoyl optionally having one or        more suitable substituent(s) (e.g., lower alkyl) such as        cyclopropyloxyacetyl, cyclobutyloxypropionyl,        cycloheptyloxybutyryl, mentyloxyacetyl, mentyloxypropionyl,        mentyloxybutyryl, mentyloxypentanoyl, mentyloxyhexanoyl and the        like,    -   camphorsulfonyl;    -   lower alkylcarbamoyl having one or more suitable substituent(s)        such as carboxy, protected carboxy and the like, such as        carboxy(lower)alkylcarbamoyl (e.g., carboxymethylcarbamoyl,        carboxyethylcarbamoyl, carboxypropylcarbamoyl,        carboxybutylcarbamoyl, carboxypentylcarbamoyl,        carboxyhexylcarbamoyl) and    -   tri(lower)alkylsilyl(lower)alkyloxycarbonyl(lower)-alkylcarbamoyl        (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl,        trimethylsilylethoxycarbonylpropylcarbamoyl,        triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyl        dimethylsilylethoxycarbonylpropylcarbamoyl,        trimethylsilylpropoxycarbonylbutylcarbamoyl).

Aromatic acyl is exemplified by aroyl optionally having suitablesubstituent(s) (e.g., nitro), such as benzoyl, toluoyl, xyloyl,naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl and the like;and arenesulfonyl optionally having one or more suitable substituent(s)(e.g., halogen), such as benzenesulfonyl, toluenesulfonyl,xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl,chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and thelike.

The aliphatic acyl substituted by aromatic group may be, for example,ar(lower)alkanoyl optionally having one or more suitable substituent(s)(e.g., lower alkyloxy, trihalo(lower)alkyl and the like), whereinspecific examples are phenylacetyl, phenylpropionyl, phenylbutyryl,2-trifluoromethyl-2-methoxy-2-phenylacetyl,2-ethyl-2-trifluoromethyl-2-phenylacetyl,2-trifluoromethyl-2-propoxy-2-phenylacetyl and the like.

Of the above-mentioned acyl, more preferable acyl includes C₁-C₄alkanoyl optionally having carboxy, cyclo(C₅-C₆)alkyloxy(C₁-C₄)alkanoylhaving two (C₁-C₄)alkyl in the cycloalkyl moiety, camphorsulfonyl,carboxy(C₁-C₄)alkylcarbamoyl,tri(C₁-C₄)alkylsilyl(C₁-C₄)alkyloxycarbonyl(C₁-C₄)alkylcarbamoyl,benzoyl optionally having 1 or 2 nitro groups, and benzenesulfonylhaving halogen, phenyl(C₁-C₄)alkanoyl having C₁-C₄ alkyloxy andtrihalo(C₁-C₄)alkyl. Of these, most preferred are acetyl,carboxypropionyl, mentyloxyacetyl, camphorsulfonyl, benzoyl,nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl,2-trifluoromethyl-2-methoxy-2-phenylacetyl and the like.

Preferable examples of the “heterocyclic group consisting of saturatedor unsaturated 5 or 6-membered ring having nitrogen atom, sulfur atomand/or oxygen atom” are pyrolyl, tetrahydrofuryl and the like.

The “heteroaryl optionally having a suitable substituents” moiety of the“heteroaryloxy optionally having a suitable substituent” is thatexemplified for R¹ of the compound of the formula I of EP-A-532088, withpreference given to 1-hydroxyethylindol-5-yl. This publication isincorporated hereinto by reference.

The tricyclo compound (I) and a pharmaceutically acceptable salt thereofto be used in the present invention have superior IL-2 inhibitory actionand immunosuppressive action, antibacterial action and otherpharmacological activity, so that they are useful for the prophylaxisand treatment of rejection in organ or tissue transplantation, graftversus host reaction, autoimmune diseases, infectious diseases and thelike, as noted, together with the production method thereof, in, forexample, EP-A-184162, EP-A-323042, EP-A-423714, EP-A-427680,EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337,EP-A-626385, WO89/05303, WO93/05058, WO96/31514, WO91/13889, WO91/19495,WO93/5059 and the like, all of these publications are herebyincorporated by reference.

In particular, the compounds called FR900506 (=FK506), FR900520(Ascomycin), FR900523 and FR900525 are produced by the genusStreptomyces, such as Streptomyces tsukubaensis, No. 9993 (depository:National Institute of Advanced Industrial Science and Technology,International Patent Organism Depositary, Central 6, 1-1 Higashi1-chome, Tsukuba-shi, Ibaraki-ken, Japan (formerly: FermentationResearch Institute, Agency of Industrial Science and Technology, theMinistry of International Trade and Industry), date of deposit: Oct. 5,1984, deposit number: FERM BP-927) or Streptomyces hygroscopicus subsp.Yakushimaensis, No. 7238 (depository: National Institute of AdvancedIndustrial Science and Technology, International Patent OrganismDepositary, Central 6, 1-1 Higashi 1-chome, Tsukuba-shi, Ibaraki-ken,Japan (formerly: Fermentation Research Institute, Agency of IndustrialScience and Technology, the Ministry of International Trade andIndustry), date of deposit: Jan. 12, 1985, deposit number: FERM BP-928(EP-A-0184162), and the compound of the following formula), FK50.6(general name: Tacrolimus) is a representative compound.

Chemical Name:17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0^(4,9)]octacos-18-ene-2,3,10,16-tetraone

Of the tricyclo compounds (I), more preferred is a compound whereinadjacent pairs of R³ and R⁴, and R⁵ and R⁶ may each independently formanother bond between carbon atoms binding with the members of eachpairs;

-   -   R⁸ and R²³ each independently show hydrogen atom;    -   R⁹ is hydroxy;    -   R¹⁰ is methyl, ethyl, propyl or allyl;    -   X is (hydrogen atom, hydrogen atom) or oxo;    -   Y is oxo;    -   R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²² each independently show        methyl;    -   R²⁴ is 3-R²⁰-4-R²¹-cyclohexyl,        -   wherein R²⁰ is hydroxy, alkyloxy or —OCH₂OCH₂CH₂OCH₃, and        -   R²¹ is hydroxy, —OCN, alkyloxy, heteroaryloxy optionally            having suitable substituent, —OCH₂OCH₂CH₂OCH₃, protected            hydroxy, chloro, bromo, iodo, aminooxalyloxy, azide,            p-tolyloxythiocarbonyloxy or R²⁵R²⁶CHCOO— (wherein R²⁵ is            hydroxy optionally protected where desired, or protected            amino, and R²⁶ is hydrogen atom or methyl), or R²⁰ and R²¹            in combination form an oxygen atom of epoxide ring; and    -   n is 1 or 2.

Particularly preferable tricyclo compound (I) include, besides FK506,Ascomycin derivatives such as halogenated derivative of33-epi-chloro-33-desoxy Ascomycin described in Example 66a ofEP-A-427,680 and the like.

Other preferable IL-2 inhibitors (macrolide compounds) include Rapamycindescribed in MERCK INDEX, 12 edition, No. 8288 and derivatives thereof.Preferable examples thereof include O-substituted derivative describedat page 1 of WO95/16691, formula A, wherein the 40^(th) hydroxy is —OR₁(wherein R₁ is hydroxyalkyl, hydroalkyloxyalkyl, acylaminoalkyl oraminoalkyl), such as 40-O-(2-hydroxy)ethyl Rapamycin,40-O-(3-hydroxy)propyl Rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylRapamycin and 40-O-(2-acetaminoethyl)Rapamycin. These O-substitutedderivatives can be produced by reacting, under appropriate conditions,Rapamycin (or dihydro or deoxo Rapamycin) and an organic radical boundwith a leaving group (e.g., RX wherein R is an organic radical desirableas O-substituent, such as alkyl, allyl and benzyl moiety, and X is aleaving group such as CCl₃C(NH)O and CF₃SO₃)). The conditions are: whenX is CCl₃C(NH)O, acidic or neutral conditions, such as in the presenceof trifluoromethanesulfonic acid, camphorsulfonic acid,p-toluenesulfonic acid or their corresponding pyridinium or substitutedpyridinium salt, and when X is CF₃SO₃, in the presence of a base such aspyridine, substituted pyridine, diisopropylethylamine andpentamethylpiperidine. The most preferable Rapamycin derivative is40-O-(2-hydroxy)ethyl Rapamycin as disclosed in WO94/09010, which ishereby incorporated into the specification by reference.

The pharmaceutically acceptable salt of tricyclo compound (I), Rapamycinand derivatives thereof are nontoxic and pharmaceutically acceptableconventional salts, which are exemplified by salts with inorganic ororganic base such as alkali metal salt (e.g., sodium salt, potassiumsalt and the like), alkaline earth metal salt (e.g., calcium salt,magnesium salt and the like), ammonium salt, and amine salt (e.g.,triethylamine salt, N-benzyl-N-methylamine salt and the like).

In the IL-2 inhibitor of the present invention, particularly macrolidecompound, conformers and one or more pairs of stereoisomers such asoptical isomers and geometric isomers, which are due to asymmetriccarbon atom and double bond, may be included. Such conformers andisomers are also encompassed in the present invention. In addition,macrolide compounds can form solvates, which case is also encompassed inthe present invention. Preferable solvate is exemplified by hydrates andethanolates.

Other IL-2 inhibitors are known from MERCK INDEX, 12^(th) ed., No. 2821,U.S. Pat. Nos. 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chim.Acta, 60, 1568 (1977) and 65, 1655 (1982) and Transplant. Proc. 17, 1362(1985) and the like. Specifically, they are cyclosporins such ascyclosporin A, B, C, D, E, F and G and derivatives thereof. Particularlypreferred is cyclosporin A. These publications are hereby incorporatedinto the specification by reference.

The tricyclo compound (I), pharmaceutically acceptable salt thereof,cyclosporins and derivatives thereof can be classified as “IL-2production inhibitor” that inhibits production of IL-2. Rapamycin andderivative thereof can be classified as “IL-2 signal transductioninhibitor” that inhibit transmission of IL-2 signal.

In the present invention, the allergic disease encompasses any reactiontype of IgE dependent anaphylactic type (I type), cytotoxic type (IItype), immune complex type (III type) and cellular immunity type (IVtype), as classified by Coombs and Gell (1963) mentioned above. Inparticular, bronchial asthma, allergic rhinitis, allergicconjunctivitis, atopic dermatitis, food allergy, drug allergy and thelike classified under I type allergy are the suitable diseases to betargeted.

The treatment in the context of the present invention includes anymanagement such as prevention, cure, alleviation of symptom, reductionof symptom, prevention of progression and the like.

By “for pre-administration” of the “pharmaceutical agent forpre-administration” and “pharmaceutical composition forpre-administration” of the present invention is meant administration inadvance in a treatment method of allergic diseases, which comprisesadministering an IL-2 inhibitor to a subject in need of a treatment ofallergic diseases for a given period of time (i.e., leading period) andthereafter again administering an effective amount of an IL-2 inhibitor.In the present specification, an IL-2 inhibitor used forpre-administration is distinguished from an IL-2 inhibitor to beadministered after the leading period for pre-administration, as an IL-2inhibitor to be used for treatment of allergic disease (to be referredto simply as during treatment).

According to the present invention, by setting a leading period forpre-administration of an IL-2 inhibitor, the effect on the allergicdiseases can be expressed in a remarkably enhanced manner. For example,since the period of onset and termination of seasonal allergic diseasesare mostly determined, a leading period for pre-administration setbefore the probable season of the onset of the disease enables moreeffective treatment of the disease. In the present invention, therefore,seasonal allergic diseases such as seasonal allergic conjunctivitis andseasonal allergic rhinitis are among the suitable target diseases. Inaddition, by setting a leading period for pre-administration, treatmentwith an IL-2 inhibitor at lower concentrations or with less frequency ofthe instillation per day, when the allergic diseases can be treated,becomes attainable thereby decreasing the burden on the patient.

According to the present invention, the above-mentioned IL-2 inhibitoris administered in an effective amount for the treatment of allergicdisease to a subject in need thereof, after the leading period forpre-administration.

The IL-2 inhibitor used in the present invention for pre-administrationand/or treatment of allergic diseases can be used as a pharmaceuticalagent for human and animals, and can be administered systemically orlocally by oral administration, intravenous administration (inclusive oftransfusion), subcutaneous administration, rectal or virginaladministration, administration to a local site of the eye (inclusive ofeye ointment), administration to a local site of the nose (inclusive ofspray). In consideration of systemic influence, significant expressionof the effect and like, it is particularly preferably used in a formsuitable for local administration.

The dosage form may be, for example, eye drop, eye ointment, nasal drop,spray, powder, granule, tablet, capsule, injection, ointment and thelike, with particular preference given to eye drop, eye ointment, nasaldrop, spray and the like. Such preparations can be produced according toconventional methods.

In the present invention, the leading period for pre-administration ofan IL-2 inhibitor varies depending on the kind, age, body weight,condition to be treated, desired therapeutic effect, administrationroute and the like of the subject to be treated, such as human andanimal. In general, the period is from 3 days to about 2 months,preferably from about 1 week to 1 month, which is determined asappropriate.

The dose of the IL-2 inhibitor during the leading period variesdepending on the kind, age, body weight, condition to be treated,desired therapeutic-effect, administration route, treatment period,leading period, and the like, with regard to the subject to be treated,such as human and animal. Generally, when it is administratedsystemically, the dose is about 0.0001-1000 mg, preferably 0.001-500 mg,which is given in a single dose or 2 to 4 dividual doses a day or in asustained manner. When it is administered locally to the eye, apreparation containing the active ingredient in a proportion of0.001-10.0 w/v %, preferably 0.005-5.0 w/v %, is applied several times aday per eye, preferably instilled or applied 1 to 6 times a day.

After the leading period for pre-administration of an IL-2 inhibitor,the dose and administration frequency of the IL-2 inhibitor for thetreatment of the allergic disease are within the range specified abovefor the leading period. According to the present invention, the presenceof the leading period enables reduction of the dose and administrationfrequency of the IL-2-inhibitor during the treatment.

The kind of the IL-2 inhibitor to be administered during the treatmentis appropriately determined depending on the condition to be treated,desired therapeutic effect, administration route, treatment period,leading period and the like. It is preferable that the same IL-2inhibitor administered during the leading period be used.

The present invention is explained in more detail in the following byway of Examples. The present invention is not limited by these Examplesin any way.

EXAMPLES Experimental Example 1

Method 1

Patients with allergic conjunctivitis (3 groups, 30 patients per group)were instilled with an antigen into the eye. Three minutes later,itchiness of the eye was evaluated in 9 levels (0, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4), and the average value (base line group) of itchiness wasdetermined. A specific antigen was determined for each patient. Theantigen determined was the one against which the patient showed highestsensitivity in the preceding confirmation test using 9 kinds of antigens(cat hair, cat dander, ragweed, birch, oak, maple, meadow fescue, rye,kentucky blue).

Method 2

At least one week was allowed to lapse from the test of Method 1, andFK506 eye drop (suspension) [0.03%, 0.06% or 0.1%] was instilled intothe eye of the patients. At 8 hr after the instillation of the eye drop,the antigen was given. Three minutes later, itchiness of the eye wasevaluated in the same manner as in Method 1, and the average value(without pre-administration) of itchiness was determined. In the groupwithout pre-administration, the proportion (improvement rate) of thepatients who showed at least 1 point lower itchiness than the base lineitchiness was determined. The results are shown in Table 1.

Method 3

At least one week was allowed to lapse from the test of Method 2, andFK506 eye drop was instilled into the eye of the patients once a day forone week. At 16 hr after the last instillation of the eye drop, theantigen was given. Three minutes later, itchiness of the eye wasevaluated in the same manner as in Method 1, and the average value (withpre-administration) of itchiness was determined. In the group withpre-administration, the proportion (improvement rate) of the patientswho showed at least 1 point lower itchiness than the base line itchinesswas determined. The results are shown in Table 1. TABLE 1 improvement(%) of improvement (%) of Drug con- group without group with centrationpre-administration pre-administration 0.03% 25.93 61.54 0.06% 40.0065.52  0.1% 56.67 72.41

INDUSTRIAL APPLICABILITY

From the above results, it is evident that the improvement effect on theitchiness can be strikingly enhanced by setting a leading period forpre-administration of FK506. For example, the improvement rate of the0.03% concentration group with pre-administration was higher than thatof the 0.1% concentration group without pre-administration. Hence, bysetting a leading period for pre-administration, the allergic diseasecan be treated with a lower concentration of a medicament. In thecomparison of 0.1% concentration groups, the improvement rate of thegroup with pre-administration after 16 hr was markedly higher than thatof the group without pre-administration after 8 hr. Hence, by setting aleading period for pre-administration, the allergic disease can betreated with less frequency of the instillation.

1-18. (canceled)
 19. A method for treating an allergic disease, whichcomprises pre-administering an interleukin 2 inhibitor for a leadingperiod and then administering an effective amount of an interleukin 2inhibitor to a subject in need of a treatment of an allergic disease.20. The method of claim 19, wherein the interleukin 2 inhibitor is amacrolide compound or a cyclosporin.
 21. The method of claim 20, whereinthe macrolide compound is a tricyclo compound (I) of the followingformula;

wherein adjacent pairs of R¹ and R², R³ and R⁴, and R⁵ and R⁶ eachindependently a) consist of two adjacent hydrogen atoms, wherein R² isoptionally alkyl, or b) form another bond between carbon atoms bindingwith the members of each pairs; R⁷ is hydrogen atom, hydroxy, alkyloxyor protected hydroxy, or may form oxo with R⁸ and R⁹ each independentlyshow hydrogen atom or hydroxy; R¹⁰ is hydrogen atom, alkyl, alkenyl,alkyl substituted by one or more hydroxy, alkenyl substituted by one ormore hydroxy, or alkyl substituted by oxo; X is oxo, (hydrogen atom,hydroxy), (hydrogen atom, hydrogen atom), or a group of the formula—CH₂O—; Y is oxo, (hydrogen atom, hydroxy), (hydrogen atom, hydrogenatom), or a group of the formula N—NR¹¹R ¹² or N—OR¹³; R¹¹ and R¹² eachindependently show hydrogen atom, alkyl, aryl or tosyl; R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²² and R²³ each independently show hydrogen atom oralkyl; R²⁴ is an optionally substituted ring that may contain one ormore hetero atom(s); and n is 1 or 2; and Y, R¹⁰ and R²³ may form,together with the carbon atom they bind with, a saturated or unsaturated5 or 6-membered heterocyclic group containing nitrogen atom, sulfur atomand/or oxygen atom, wherein the heterocyclic group may be substituted byone or more group(s) selected from the group consisting of alkyl,hydroxy, alkyloxy, benzyl, a group of the formula —CH₂Se(C₆H₅), andalkyl substituted by one or more hydroxy, or a pharmaceuticallyacceptable salt thereof.
 22. The method of claim 20, wherein themacrolide compound is FK506.
 23. The method of clam 19, wherein theinterleukin 2 inhibitor is a preparation for local administration. 24.The method of clam 23, wherein the local administration isadministration to the eye or to the nose.
 25. The method of claim 19,wherein the allergic disease is allergic conjunctivitis.
 26. The methodof claim 19, wherein the allergic disease is seasonal allergic disease.27. The method of claim 26, wherein the seasonal allergic disease isseasonal allergic conjunctivitis. 28-37. (canceled)
 38. The method ofclaim 21, wherein the macrolide compound is FK506.